PROJECT SUMMARY: The Neuroscience Research CORE (CORE B) is divided into a Tissue Culture/Animal SubCore and a Crystallography/Molecular Modeling SubCore. The objective of the Tissue Culture/Animal SubCore is to provide each ofthe projects with assistance in mouse breeding/genotyping, cell culture and related experiments, and to provide large items of equipment for common use. The cost-effectiveness of the Core is achieved by having a core serve all 3 projects in order to eliminate duplication of effort. For example, in the Neuroscience Core, skilled technicians produce a variety of high quality neuronal cultures derived from primary tissues or stem cells, particulariy neurons from valuable fetal brain and iPSCs from human Down syndrome (DS), which will allow us to study the effect of NMDA receptors (NMDARs) and related molecules in DS. The objective of the Crystallography/Molecular Modeling SubCore is to use two types of structural approaches, crystallography and molecular modeling, to assist us in elucidating the mechanism of NMDAR activation and, consequently, in designing improved drugs that can modulate NMDARs for neuroprotection. Crystallography will provide structural information on the NMDAR at atomic resolution and molecular modeling will provide a framework to predict and interpret perturbations of receptor function by mutations or drugs when direct experimental data (i.e., crystal structures) are as yet unavailable. The multi-disciplinary approach provided by this Core is critical for solving the complex problem of structure-function analysis of NMDARs in this Program Prbject and how this information can be harnessed for protecting synaptic integrity in DS. Integrated leadership in the Core is achieved by Dr. Zhang attending to the day-to-day activities ofthe Core, for which he has 14 years of experience, while Dr. Lipton oversees the overall mission, interactions, and relevance of the Core to each project. The Scientific Core enables the work of all 3 projects in this Program Project Grant, and draws upon the tissue culture, animal breeding, and stem cell knowledge in Dr. Lipton's laboratory as well as the crystallography and modeling expertise of Drs. Zhang, Jin and Godzik, in conjunction with the considerable molecular and genetic experience of Dr. Nakanishi.